Exposure to a reduced-nutrient diet without malnutrition, or dietary restriction (DR), is known to delay the onset and progression of physiological and behavioral decline over time. Dietary protein has been implicated as a key macronutrient that mediates life-extension by DR. Interestingly, research done in an invertebrate model, Drosophila melanogaster, has revealed that exposure to the smell of a major protein source, dietary yeast in the case of Drosophila, is sufficient to limit the benefits of DR on lifespan. This study evoked an exciting possibility that sensory perception of dietary protein plays a role in the modulation of aging. However, knowledge about how sensory information is processed or how it initiates widespread changes in physiology, including aging, remains rudimentary. The major objectives of this proposal are to establish neurosensory mechanisms of dietary protein perception and to evaluate its role in life-extension by DR. Our preliminary data, together with recently published results, suggested that serotonin, an important neurotransmitter, may be a key player in distinguishing protein in a food. To elucidate the specific mechanisms underlying how dietary proteins are perceived and how the relevant sensory signals are represented in the central nervous system (CNS), we will undertake careful dissection of serotonin signaling pathways using powerful genetic and neuroscience tools available in Drosophila research. We will then advance our knowledge in how sensory perception of dietary protein orchestrates global physiological changes by uncovering neuroendocrine cells that mediate dietary protein-evoked serotonin signaling. Comprehensive knowledge we gathered from these experiments will put us in a uniquely strong position to test a functional link between perception of dietary protein and diet-mediated longevity extension through serotonin signaling. The findings from our proposed studies will bring new insights into basic biology and clinical geriatric research. First, establishing connectivity between the functio of the CNS and diet-dependent longevity in fruit flies will provide a basic framework to examine similar mechanisms in more complex organisms. Second, understanding how nutrient signals are perceived and how this information is processed will foster clinical research to target neurological regulation of nutrient intake or age-associated disease progression.